Sethuramani A et al / Int. J. Res.

Pharmacology & Pharmacotherapeutics, 13(4) 2024 [495-504]

International Journal of Research in

Pharmacology & Pharmacotherapeutics (IJRPP)
IJRPP |Vol.13 | Issue 4 | Oct - Dec -2024
www.ijrpp.com
ISSN: 2278-2648 DOI : h ps://doi.org/10.61096/ijrpp.v13.iss4.2024.495-504

Review

Comprehensive Review of Asthma: Pathophysiology, Genetic Influences,

and Emerging Treatment Strategies
Sethuramani A1*, Chandrasamy M2, Ajith P2, Saranya S2, Sasikumar A2, T. Venkata
Rathina Kumar3
1
Assistant Professor, Department of Pharmacognosy, College of Pharmacy, Madurai Medical College,
Madurai, Tamil Nadu, India.
2
Department of Pharmacognosy, College of Pharmacy, Madurai Medical College, Madurai, Tamil
Nadu, India
3
Principal, College of Pharmacy, Madurai Medical College, Madurai, Tamil Nadu, India

*Author for Correspondence: Sethuramani A

Email: [email protected]

Abstract
The review article provides an in-depth exploration of asthma, a chronic
Published on: 05 Nov 2024 inflammatory disease influenced by a complex interplay of genetic and
environmental factors. It traces the historical development of asthma's
definition and diagnosis, from early medical descriptions to modern
Published by: epidemiological studies that reveal its rising prevalence. The article discusses
DrSriram Publications the pathophysiology of asthma, focusing on immune responses involving T
helper type 2 (Th2) cells and cytokines, along with molecular mechanisms like
2024| All rights reserved. IgE production and airway remodeling. Genetic factors, such as mutations in
the ADAM33 and filaggrin genes, are examined for their role in asthma
susceptibility and disease progression. Different asthma types—such as adult-
onset, exercise-induced, and cough-induced—are reviewed, highlighting their
unique triggers and diagnostic challenges. Treatment strategies, including
Creative Commons conventional medications (inhaled corticosteroids, β2-agonists) and alternative
Attribution 4.0 International therapies (phytochemicals), are evaluated, along with the limitations of current
License. treatments and the need for improved therapeutic options. The article
underscores the importance of personalized approaches to asthma management
based on individual genetic and environmental profiles.

Keywords: Asthma, inflammation, treatment, medicinal plant

INTRODUCTION
Since the word "asthma" comes from the Greek for "short of breath," any patient who experienced
dyspnea was diagnosed with asthma. Henry Hyde Salter's dissertation "On Asthma and its Treatment," which was
published in the second half of the 19th century, helped to refine the word. Salter described asthma in this
academic work as "Paroxysmal dyspnea of a peculiar character with intervals of healthy respiration between
attacks," which perfectly encapsulates his idea of a condition in which the smooth muscle in the airways contracts,
narrowing the airways.(1) About 30 years before Paul Ehrlich established aniline stains for eosinophils (eosin)

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and mast cells (toluidine blue), his book includes surprisingly accurate pictures of the airways in asthma and
bronchitis as well as the cellular appearance of asthmatic sputum. Additionally, he explained that black coffee, a
beverage that contains a lot of theobromine, a byproduct of theophylline, and theophylline itself, can be used to
relieve asthmatic spasms. Because Dr. Salter has asthma himself, he has a unique perspective on the condition.
By the late nineteenth century, doctors therefore came to believe that asthma was a unique illness with a particular
set of causes, clinical implications, and therapeutic needs.(2,3)

Asthma
Asthma, conventionally defined as chronic inflammatory disease caused by a large number of gene
environment interplays, manifests with variable airway obstruction and bronchial hyperresponsiveness, ultimately
causing cough, wheeze, shortness of breath, and chest tightness.(4,5) Frequent triggers of asthma episodes include
viral infections, exposure to allergens and/or pollutants, cigarette smoking, sudden temperature variations, stress,
and exercise among others. Patients with persistent asthma disease shall be subjected to more aggressive care,
aimed at lowering an otherwise high risk of developing important—often life-threatening complications, such as
enhanced vulnerability to respiratory infections, pneumothorax, emphysema, loss of lung function, respiratory
failure, up to death. (6)

Epidemiology
During the second half of the Twentieth century, notably since the 1960s, a sharp increase in asthma
prevalence was observed in a number of developed countries. This observation was a result of repeated cross-
sectional surveys of prevalence of asthma, mainly in children but also in adults. As a result of this observation, in
the 1990s, a series of epidemiological studies were established across the world to estimate global asthma
prevalence and incidence, and identify risk factors associated with these outcomes. These include large
multinational studies in children [such as the International Study of Asthma and Allergies in Childhood (ISAAC;
http://isaac.auckland.ac.nz/) (7–8)] and in adults [such as the European Community Respiratory Health Survey
(ECRHS; http://www.ecrhs.org/) (9)]. These studies confirmed that asthma is one of the most common chronic
diseases across the globe in all age groups and there is substantial variation in asthma prevalence worldwide.
It is now acknowledged that the prevalence of both childhood and adult asthma may have peaked in some
areas, predominantly in high-income countries, whereas an increase may be continuing in low and mid-income
countries (10). It is important to note that a reduction in the prevalence of current asthma is determined by
improved asthma control and/or reduced asthma incidence at a population level. Thus, a reduction in prevalence
of current asthma may well-reflect improved asthma control through increased medication use from more
widespread prescribing habits and better compliance. Documenting reductions in asthma incidence is complicated
as parallel cohort studies with specific age windows are needed to establish patterns with the comparison group
ideally from the same geographical region. These challenges might in part explain why studies from Australia and
UK have not consistently shown reductions in asthma prevalence and why temporal trends in European and Asian
countries between the 1970s and mid-2000s have been conflicting. (11)

Types of asthma
Adult-onset asthma
The term used for asthma that emerges after the age of 20 is adult-onset asthma. This condition tends to
impact women more than men and is notably less prevalent compared to childhood-onset asthma. Allergies can
also act as triggers for adult-onset asthma. It's estimated that as much as 50% of adult-onset asthma cases are
associated with allergic reactions.(12,13)

Exercise-induced asthma
Exercise-induced asthma refers to symptoms such as coughing, wheezing, or breathlessness experienced
during or after physical exertion. The level of fitness plays a significant role in this condition. An individual who
is not physically fit and engages in intense exercise, like running for ten minutes at a fast pace, is likely to
experience breathlessness, which can mimic symptoms of asthma

Cough-induced asthma
Diagnosing cough-induced asthma presents a significant challenge for doctors. They must systematically
rule out other potential causes, such as chronic bronchitis, post-nasal drip from hay fever, or sinus disease. In
cases of cough-induced asthma, coughing may occur independently, without accompanying asthma symptoms.
Moreover, the coughing episodes can manifest at any time, day or night, potentially disrupting sleep if they occur
during nighttime.

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Occupational asthma
Occupational asthma arises from triggers present in the patient's workplace environment. These triggers
encompass a range of factors including chemicals, vapors, gases, smoke, dust, fumes, or other particles.
Additionally, asthma episodes can be instigated by viral infections like the flu, molds, animal products, pollen,
fluctuations in humidity and temperature, and even stress.

Causes of asthma (14)

Genes

Allergies

Environmental Factors

Tobacco smoke

Fig 1: Causes of asthma

Pathophisiology
Asthma is linked with T helper cell type-2 (Th2) immune responses, akin to those observed in other
atopic disorders. Triggers for asthma include a spectrum of allergic factors such as dust mites, cockroach residue,
pet dander, molds, and pollens. Moreover, non-allergic factors like infections, exposure to tobacco smoke, cold
air, and physical exertion can also provoke asthma symptoms. Triggers set off a chain of immune-mediated
responses culminating in chronic inflammation of the airways Elevated levels of Th2 cells within the airways
release specific cytokines, notably interleukin (IL)-4, IL-5, IL-9, and IL-13. These cytokines promote eosinophilic
inflammation and stimulate mast cells to produce immunoglobulin E (IgE). IgE production, in turn, prompts the
release of inflammatory mediators like histamine and cysteinyl leukotrienes. These mediators induce
bronchospasm (smooth muscle contraction in the airways), edema (swelling), and increased mucous secretion
(mucous hypersecretion), thereby eliciting the hallmark symptoms of asthma. (15,16)

Fig 2: Pathophysiology of asthma

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Molecular mechanism of bronchial asthma

In recent years, much work has been done to help deepen our understanding of the molecular mechanisms
of bronchial asthma. Chief among them is the molecular differences that split the mechanism of asthma into two
distinct Asthma.
Type 2 asthma, is bronchial asthma in which type 2 helper T (Th2) cytokines, such as interleukin-4 (IL-
4), IL-5, and IL-13 increase; Th2 cytokines play an important role in its pathophysiology, hence the term type 2
Th2 cytokines are produced not only by Th2 cells but also by basophils, mast cells, and type 2 innate lymphoid
cells (ILC2s).(17,18)Antigen presenting cells (APCs) such as dendritic cells (DCs) and macrophages phagocyte
the antigen and move to the regional lymph node, in which they deliver an antigen peptide to naive T cells via
MHC class II switch (antigen presentation). Antigen stimulation differentiates naive T cells into Th2 cells. Th2
cells activate B cells to produce immunoglobulin E (IgE). The IgE produced binds the high-affinity IgE receptor
(FcεRI) on the cell surface of the mast cell (sensitization). (19,20)
When the invading antigen binds to antigen-specific IgE on mast cells, the mast cells release mediators
(degranulation). This early-phase reaction occurs within minutes after antigen exposure. The released mediators
consist of histamine, prostaglandin, leukotriene and several cytokines such as IL-8, IL- 13, tumor necrosis factor
(TNF)-a and chemokine (CeC motif) ligand (CCL) 2 . These mediators induce mucus production, broncho-
constriction, and the recruitment of leukocytes such as neutrophil, lymphocyte, and eosinophil. In mice,
eosinophils are divided into two subtypes based on the expression of surface markers: resident eosinophils (rEos)
residing in the lungs and inflammatory eosinophils (iEos) induced in the lungs during inflammation In the late-
phase reaction, which occurs hours after antigen exposure, the iEos release several cytokines, which induce
bronchoconstriction and epithelial cell damage, leading to airway hyperresponsiveness (AHR) and tissue
remodeling However, these subtypes and specific mechanisms of eosinophils are yet to be fully confirmed in
humans(21)

Fig 3: Mechanism of asthma

Molecular genetics of asthma

Over a hundred different genes have been associated with asthma and the list is still growing. Asthma
susceptibility genes fall mainly into three categories relating to 1) functioning of the immune system, 2) mucosal
biology and function, and 3) lung function and disease expression. However, just because a gene has been
associated with asthma in a single study does not necessarily establish a connection between that gene and the
disease.
A major problem in many genetic studies of asthma is the lack of replication of results from previous
studies. Notably, only a subset of identified genes has been found to be associated with asthma in more than one
study; and many regard replication as one of the most important features of a gene’s candidacy. However, some
genes may be important only in a subset of asthmatics, for example, in childhood-onset asthma, atopic asthma,
house dust mite sensitive asthma, or occupational asthma, and therefore replication across these different
populations cannot always be expected. Moreover, some genes are expressed only in certain environmental

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contexts, for instance, in children growing up with a cat or in those exposed to passive smoking in the first years
of life(22,23)

ADAM33
A disintegrin and metalloproteinase 33 (ADAM33) was the first positionally cloned asthma susceptibility
gene, meaning that its exact position in the genome was identified before knowing about the function of the gene.
(24) ADAM33 is located on chromosome 20p13 and is expressed in bronchial smooth muscle cells and lung
fibroblasts. When initially discovered in 2002, it was shown to be strongly linked both to asthma and bronchial
hyperresponsiveness. (25) More recently its role has been extended to also involve more subtle aspects of asthma
pathogenesis, such as airway remodelling, progression of disease and also chronic obstructive pulmonary disease

Filaggrin
Filaggrin is a protein that helps maintain an effective skin barrier. Loss-of-function mutations in the
filaggrin gene situated on chromosome 1q21 were first associated with the skin disease ichthyosis vulgaris and
more recently with atopic dermatitis. Mutations are present in a little under 10% of individuals from Western
populations and in up to 50% of individuals with atopic dermatitis.(26,27) It is considered the strongest genetic
determinant of atopic dermatitis, increasing the risk about four-fold Moreover, filaggrin mutations have been
associated with development of allergic sensitisation, hay fever, and asthma, but only in subjects with atopic
dermatitis Interestingly, studies have found that dysfunction of the skin barrier not only enhances sensitisation to
allergens but also leads to systemic allergic responses, such as increased IgE levels and airway
hyperresponsiveness, indicating that absorption of allergens through the skin of patients with atopic dermatitis is
a prerequisite for the development of other allergic conditions, such as asthma and hay fever. (28,29,30)

Diagnosis

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The first diagnostic test should be forced expiratory spirometry, categorized as obstructed (ratio of forced
expiratory volume in first second of expiration [FEV1] to forced vital capacity [FVC] less than lower limit of
normal) or not obstructed. If airway obstruction is present, a bronchodilator response following 2 to 4 puffs of
short-acting β2-agonist should be determined. Fixed or partially reversible airway obstructionsuggests alternative
diagnoses, although severe asthma may be present. PC20 indicates the methacholine concentration required to
achieve a 20% decrease in FEV1.(31,32)

Differential diagnosis of asthma

Upper respiratory tract
 Vocal cord dysfunction
 Congestive rhinopathy
 Obstructive sleep apnea syndrome

Lower respiratory tract

 Chronic obstructive pulmonary disease
 Occupational bronchitis
 Cystic fibrosis
 Bronchiectasis
 Pneumonia
Gastrointestinal tract
Gastroesophageal reflux disease
Cardiovascular system
 Congestive heart failure
 Pulmonary hypertension
 Chronic thromboembolic pulmonary disease
Central nervous system
 Habitual cough.

Current treatments
Asthma is a chronic inflammatory airway disease arising from a complex interaction between the
immune system and resident cells of the lung to induce the cardinal features of bronchial hyper-responsiveness,
increased mucus production, narrowing of the airways and airway re modelling. A detailed review of the
pathophysiology of asthma has been covered extensively elsewhere and is outside the scope of our article
[33,34,35). The most important clinical consequences of this inflammatory process are the exacerbations of
disease causing airway narrowing and debilitating bouts of shortness of breath, wheezing, chest tightness and
cough. Most asthma treatments aim to control these symptoms and reduce the frequency of exacerbations and
current recommendations advocate the use of anti-inflammatory treatments, in particular inhaled corticosteroids
(ICS) and bronchodilators such as short and long acting β2-adrenergic agonists (LABA; 5). However, there is
concern around the inappropriate use of asthma medications, in particular the overuse of inhaled corticosteroids
in children, which can effect bone growth, and the inappropriate use of long acting bronchodilator therapy in
isolation which has been associated with increased morbidity [36]. As well as the risk of these possible adverse
effects not all patients respond to these treatments and non-adherence to treatment is common due to issues such
as complex treatment regimens, poor inhalation technique and delayed results [37] thus there is an unmet medical
need for complementary therapies for asthma.

Commonly used drugs in the management of

Asthma
 β2-Agonists
 Short-acting
- Albuterol
- Levalbuterol
 Long-acting
- Formoterol
- Salmeterol
 Theophylline
 Anticholinergics
- Ipratropium
- Tiatropium
 Anti-inflammatory agents
 Inhaled corticosteroids

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- Beclomethasone
- Budesonide
- Ciclesonide
- Flunisolide
- Fluticasone
- Mometasone
- Triamcinolone
 Cromolyn
 Leukotriene receptor modifiers
- Montelukast
- Zafirlukast
- /Zileuton
 IgE binding antibodies
- Omalizumab

Phytochemicals used for management of asthma

Table 1: Phytochemicals used for management of asthma

S.No Bio Active Compounds Activity And Potential Mechanisms Of Effect

I) POLYPHENOLS
Flavans Donation of hydrogen atom to radicals
Flavanones Chelation of redox-active metals
Isoflavanones Inhibition of lipid peroxidation
Flavones Regulation of the enzyme activities
Isoflavones Inhibition of mast cell/basophil activation
Anthocyanidins Switching allergic immune response to Th1 profile
Chalcones Regulation of various transcription factors and mediators
Flavonolignans involving angiogenesis: HIF-1, VEGF, MMPs, EGFR and
inhibit NF-κB, PI3K/Akt, and ERK1/2 signaling pathways
CURCUMIN Prevention of lipid peroxidation
RESERVATROL Inducing and stabilizing antioxidant enzymes

Table 2: Some adverse effects of current orthodox treatments for asthma

Orthodox Drug Common Adverse Effects Encountered

Isoprenaline Tachycardia
Salbutamol Muscle tremors (dose related), palpitation, restlessness, nervousness, throat
irritation and ankle edema
Theophylline Convulsions, shock, arrhythmias, increased muscle tone, tachapnoea, (dose
dependent) flushing, hypotension, restlessness, tremors, vomiting, palpitation,
diuresis, dyspepsia, insomnia etc.
Anticholinergics Dry mouth, difficulty in swallowing and talking, scarlet rash, photophobia,
blurring of near (Atropine and its congeners) vision, palpitation, ataxia,
delirium, hallucinations, hypotension, weak and rapid pulse, cardiovascular
collapse with respiratory depression, convulsions and coma (in severe
poisoning).
Ketotifen Sedation, dizziness, dry mouth, nausea and weight gain.
Corticosteroids Cushing's habitus, fragile skin, purple striae, hyperglycemia, muscular
weakness, susceptibility to infection, delayed healing of wounds and surgical
incisions, peptic ulceration, osteoporosis, glaucoma, growth retardation,
psychiatric disturbances, suppression of hypothalamo-pituitary-adrenal (HPA)
axis etc.

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Table 3: Medicinal plants used in the management of asthma

Botanical Name (Family) Common Name Extract/compound Model Reference

Aerva lanta (Amaranthaceae) Mountain Ethanol A [18]
knotgrass
Abrus precatorius Love pea Ethanol b.c [27][28]
(Papilionaceae)
Aegle marmelos (Rutaceae) Golden apple Alcoholic extract of the H [32]
leaves
Alstonia scholaris Black board tree. Ethanol extracts of leaves G (33)
(Apocynaceae) Indian devil tree
Casuarina equisetifolia Australian pine Methanol extract of extracts a.b.g (35)
(Casuarinaceae) of wood and bark
Clerodendrum serratum Glory bower. bag Ethanol extract of roots a.d (36)
(Verbenaceae) flower
Clerodendrum serratum Glory bower. bag Ethanol extract of roots a.d (36)
(Verbenaceae) flower
Crinum glaucum Poison bulb Aqucous extract b.c (26)
(AmaryHidaceae)
Curculigo orchioides Gaertn Golden eye grass Alcoholic extract of rhizome a,b.d.e.f. [27]
(Amaryllidaceae)
Camellia sinensis (Theaceae) Tea plant. tea Tea-leaf saponins b.f [28]
shrub
Eclipta alba (Asteraceae) False daisy Ethanol extract b.f 1391
Euphorbia hirta Asthma plant Ethanol extract of aerial part B (20)
(Euphorbiaceac) of the plant
Garcinia kola (Guttiferae) Bitter kola Phenols, alkaloids, xanthones [29]
and flavonoids
Hemidesmus indicus Nannari Ethanol extract A [36]
(Asclepiadaceae)
Mimosa pudica(leguminosac) Sensitive plant Ethanol extract F (NO)
Momordica dioica Balsam pear Aqueous and methanol of A (17)
(Curcubitaceae) fruit

CONCLUSION

The contents up, this review offers an in-depth examination of asthma, looking at its intricate pathophysiology,
inherited tendencies, and environmental triggers. It emphasizes how the deeper mechanisms of asthma,
specifically those related to immune system responses and certain gene alterations, influence the onset and
individual heterogeneity of the disease. The study emphasizes the value of a customized strategy to asthma
management by examining both established and new treatment approaches. Considering therapeutic advances,
the review emphasizes the need for new, more potent treatments because of the shortcomings of existing drugs
and issues with patient adherence. In order to obtain the strongest possible control of asthma, it typically advocates
a balanced mix of conventional and alternative therapy.

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